Lizomak 600

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIZOMAK 600

Composition:

Active substance: linezolid;

1 film-coated tablet contains 600 mg of linezolid;

Excipients: microcrystalline cellulose; sodium starch glycolate (type A); povidone; polyoxyl 40 hydrogenated castor oil; crospovidone; colloidal anhydrous silicon dioxide; magnesium stearate; hydroxypropylmethylcellulose; talc; titanium dioxide (E 171); polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex capsule-shaped tablets, film-coated, white to almost white, smooth on both sides.

Pharmacotherapeutic group.

Antibacterials for systemic use. ATC code J01X X08.

Pharmacological properties.

Pharmacodynamics.

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobial drugs – oxazolidinones. It is active in vitro against aerobic gram-positive bacteria, some gram-negative bacteria, and anaerobic microorganisms. Linezolid selectively inhibits protein synthesis in bacterial cells through a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S subunit of 50S) and interferes with the formation of the functional 70S initiation complex, which is an essential component of the translation process. In vitro, the post-antibiotic effect (PAE) of linezolid against Staphylococcus aureus is approximately 2 hours. In in vivo animal models, the PAE was 3.6 and 3.9 hours against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In in vivo studies, the key pharmacodynamic parameter for efficacy was the duration of time during which plasma concentrations of linezolid exceeded the minimum inhibitory concentration (MIC) for the infecting organism.

Susceptibility

The prevalence of acquired resistance in specific bacterial species may vary geographically and over time. When local resistance patterns are such that the clinical benefit of the medicinal product is uncertain, at least for certain types of infections, consultation with an expert is recommended.

Susceptible organisms

Gram-positive aerobic microorganisms: Enterococcus faecalis Enterococcus faecium* Staphylococcus aureus* Coagulase-negative staphylococci Streptococcus agalactiae* Streptococcus pneumoniae* Streptococcus pyogenes* Group C streptococci Group G streptococci Gram-positive anaerobic microorganisms: Clostridium perfringens Peptostreptococcus anaerobius Peptostreptococcus species

Resistant organisms

Haemophilus influenzae Moraxella catarrhalis Neisseria species Enterobacteriaceae Pseudomonas species

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

Linezolid has shown some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae in studies; however, data are insufficient to confirm clinical efficacy.

Resistance

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical isolates (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

Reduced susceptibility to linezolid has been observed during treatment of patients with difficult-to-treat infections and/or with prolonged duration of therapy. Resistance to linezolid has been reported in enterococci, Staphylococcus aureus, and coagulase-negative staphylococci. This usually occurred in association with prolonged treatment courses and the presence of prosthetic materials or untreated abscesses. In the case of emergence of antibiotic-resistant bacteria in a hospital setting, appropriate measures should be taken to prevent the spread of such strains.

Pharmacokinetics

Lizomak 600 contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is rapidly absorbed after oral administration. Maximum plasma concentration (Cmax) is achieved approximately within 1–2 hours after dosing, and absolute bioavailability is approximately 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

Linezolid can be administered regardless of food intake. Time to reach maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is taken with a high-fat meal. However, total exposure, assessed by AUC0–∞, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, and this binding is independent of drug concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L.

After multiple dosing, linezolid concentrations were measured in various fluids in a limited number of healthy volunteers in Phase 1 studies. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Formation of metabolite A is believed to occur via an enzymatic pathway, whereas metabolite B formation is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, possibly involving the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully characterized.

Excretion

Non-renal clearance accounts for approximately 65% of total linezolid clearance. At steady state, approximately 30% of the dose is recovered in urine as unchanged linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating tubular reabsorption. Linezolid is hardly detectable in feces, whereas approximately 6% of the dose is recovered in feces as metabolite B and 3% as metabolite A.

A slight nonlinearity in clearance was observed with increasing linezolid doses, likely due to lower renal and non-renal clearance at higher concentrations of the drug. However, this difference in clearance was minor and did not affect the apparent half-life.

Patients with renal impairment. The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, the two main metabolites of linezolid accumulate in patients with renal impairment, with increasing accumulation observed in patients with more severe renal dysfunction. The pharmacokinetics of linezolid and its two metabolites were also studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In an ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since plasma concentrations of linezolid are similar regardless of renal function, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the main metabolites, the benefits and potential risks of linezolid use in patients with renal impairment, including the potential for metabolite accumulation, should be carefully considered. Both linezolid and its metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on linezolid pharmacokinetics is lacking.

Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. Pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Children (under 18 years of age). In children (12 to 17 years of age), the pharmacokinetics of linezolid are similar to those in adults when administered at a dose of 600 mg. Thus, adolescents receiving 600 mg every 12 hours will have exposure comparable to that in adults receiving the same dose.

In children aged 1 week to 12 years, administration of 10 mg/kg every 8 hours provides exposure approaching that achieved in adults receiving 600 mg twice daily.

In neonates up to 1 week of age, systemic clearance of linezolid (adjusted for body weight) increases rapidly during the first week of life. Therefore, neonates receiving linezolid at 10 mg/kg every 8 hours will have higher systemic exposure on the first day of life. However, excessive accumulation of the drug is not expected during the first week of life with this dosing regimen, as drug clearance increases rapidly during this period.

Elderly patients. The pharmacokinetics of linezolid in individuals aged 65 years and older are not substantially altered.

Women. Women have a lower volume of distribution compared to men, and mean clearance (adjusted for body weight) is reduced by approximately 20%. Plasma concentrations of linezolid are higher in women, which may be partially explained by differences in body weight. However, since the mean half-life values in men and women do not differ significantly, plasma concentrations in women are not expected to substantially exceed those well tolerated; therefore, dose adjustment is not required.

Clinical characteristics.

Indications.

Treatment of infections caused by susceptible microorganisms in the following conditions:

• nosocomial pneumonia;
• community-acquired pneumonia;
• complicated skin and soft tissue infections, including infections associated with diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae (the medicinal product has not been studied in the treatment of pressure ulcers);
• uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-susceptible isolates) or Streptococcus pyogenes;
• vancomycin-resistant infections caused by Enterococcus faecium strains, including infections associated with bacteremia. The medicinal product is not indicated for the treatment of infections caused by Gram-negative microorganisms. In case of suspected or confirmed Gram-negative pathogen, specific Gram-negative therapy should be initiated immediately.

Contraindications.

Hypersensitivity to linezolid or to any other component of the medicinal product. Linezolid must not be administered to patients receiving any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after discontinuation of such agents.

Except when close monitoring and blood pressure surveillance are possible, linezolid should not be administered to patients with concomitant clinical conditions such as uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness, or concurrently with any of the following medicinal products:

serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 serotonin receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic compounds (dopamine, dobutamine), meperidine, or buspirone.

Breastfeeding should be discontinued during treatment with the medicinal product (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors (MAO)

Linezolid is a weak, reversible, non-selective inhibitor of MAO. Data from drug interaction and safety studies of linezolid co-administered with medicinal products that may inhibit MAO are limited. Therefore, use of the medicinal product is not recommended, except when close patient monitoring is possible.

Potential interactions leading to increased blood pressure

In normotensive healthy volunteers receiving linezolid, a slight transient enhancement of the pressor effect of pseudoephedrine hydrochloride or phenylpropanolamine hydrochloride was observed. Concomitant administration of linezolid and pseudoephedrine or phenylpropanolamine resulted in an average increase in systolic blood pressure of 30–40 mm Hg, compared with an increase of 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies in patients with hypertension have not been conducted. It is recommended to reduce the initial dose of adrenergic agents such as dopamine or dopamine agonists and titrate gradually to achieve the desired clinical response. Very rare cases of serotonin syndrome have been reported with concomitant use of linezolid and serotonergic agents.

Potential serotonergic interactions

No symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, pathological flushing, diaphoresis, hyperpyrexia) were observed when dextromethorphan (two 20 mg doses administered 4 hours apart) was administered in combination with linezolid. One case of symptoms resembling serotonin syndrome has been reported in a patient receiving linezolid and dextromethorphan; symptoms resolved after discontinuation of both medicinal products.

During clinical use of linezolid in combination with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been described. Although concomitant use of these medicinal products is contraindicated (see section "Contraindications"), management of patients for whom treatment with both linezolid and serotonergic agents is essential is described in the section "Special precautions for use".

Use in combination with tyramine-rich foods

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This suggests that only excessive consumption of foods and beverages high in tyramine (aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soybean products such as soy sauce) should be avoided.

Medicinal products metabolized by cytochrome P450

Linezolid is not an inducer of cytochrome P450 (CYP450). Furthermore, linezolid does not inhibit the activity of clinically significant CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in humans. Therefore, an effect of linezolid on the pharmacokinetics of other medicinal products metabolized by these major enzymes is not expected.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) in combination with rifampicin (600 mg once daily for 8 days) and without. Rifampicin reduced Cmax and AUC of linezolid by an average of 21% (90% CI: 15, 27) and 32% (90% CI: 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin

When warfarin was added to a course of linezolid at steady state, a 10% reduction in mean maximum international normalized ratio (INR) was observed during concomitant administration, with a 5% reduction in INR AUC. Data on patients receiving warfarin and linezolid concurrently are insufficient to assess clinical significance, if any.

Antibiotics: aztreonam or gentamicin

The pharmacokinetics of linezolid were not altered when administered concomitantly with aztreonam or gentamicin.

In vitro studies demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampicin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.

Antioxidants

No dose adjustment of linezolid is recommended when administered concomitantly with vitamin C or E.

Strong inducers of CYP 3A4

Rifampicin: concomitant administration of rifampicin and linezolid resulted in a 21% reduction in Cmax of linezolid and a 32% reduction in AUC of linezolid. The clinical significance of this interaction has not been established. The mechanism of this interaction is not fully understood and may be related to induction of hepatic enzymes.

Special precautions for use.

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO), but at doses used for antibacterial therapy, the drug does not exhibit antidepressant effects. Data on drug interactions and safety when administered to patients with concomitant diseases or those receiving concomitant medications that may inhibit MAO are limited. Therefore, under such circumstances, the drug is not recommended except when close patient monitoring is possible.

Patients should be advised to avoid consuming foods high in tyramine.

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in some patients receiving linezolid. After discontinuation of linezolid, abnormal hematological parameters returned to pre-treatment levels. In elderly patients, use of linezolid is associated with a higher risk of hematological abnormalities compared to younger patients. An increased frequency of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate to severe hepatic impairment. Therefore, careful monitoring of blood counts is necessary in the following patient groups: patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications capable of reducing hemoglobin levels, decreasing blood cell counts, or negatively affecting platelet number or function; patients with severe renal impairment; patients with moderate to severe hepatic impairment; and patients receiving treatment for more than 10–14 days. Linezolid should be used in such patients in conjunction with careful monitoring of hemoglobin levels, complete blood count, and, where possible, platelet count.

If significant myelosuppression develops during treatment with linezolid, therapy should be discontinued unless continuation is deemed absolutely necessary. In such cases, careful monitoring of complete blood count parameters and appropriate therapeutic interventions are required.

Additionally, weekly complete blood counts (including hemoglobin, platelet count, total white blood cell count, and differential leukocyte count) are recommended for all patients receiving linezolid, regardless of baseline blood parameters.

Sideroblastic anemia

In patients receiving linezolid for more than 28 days (the maximum recommended treatment duration), an increased incidence of severe anemia has been observed. Such patients more frequently required blood transfusions. Cases of sideroblastic anemia have also been reported. After discontinuation of linezolid, most patients recovered fully or partially with treatment for anemia or even without treatment.

Mortality imbalance in a clinical trial involving patients with catheter-related bloodstream infections caused by Gram-positive pathogens

In an open-label study of patients with serious catheter-related bloodstream infections, an increased mortality rate was observed in the group receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (78 of 363 (21.5%) vs. 58 of 363 (16.0%)). The primary factor influencing mortality was the presence of Gram-positive infection at baseline.

Mortality rates in patients with infections caused exclusively by Gram-positive organisms were similar (relative risk 0.96; 95% CI: 0.58–1.59), but in the linezolid treatment group, mortality was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen identified at baseline (relative risk 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the investigational drug. Most patients in the linezolid group developed Gram-negative infections during the study and died from infections caused by Gram-negative pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with established or suspected concomitant Gram-negative infection, linezolid should be used only if no other treatment options are available (see section "Indications"). In such cases, concomitant treatment for Gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis

Cases of pseudomembranous colitis have been reported with the use of nearly all antibacterial agents, including linezolid. Therefore, it is important to consider this diagnosis in patients who develop diarrhea after administration of any antibacterial agent. If antibiotic-associated colitis is suspected or confirmed, discontinuation of linezolid and appropriate management measures may be warranted.

Diarrhea and colitis associated with antibiotic use, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with the use of nearly all antibacterial agents, including linezolid, with severity ranging from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or colitis is suspected or confirmed, current antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures initiated immediately. In such situations, the use of agents that inhibit peristalsis is contraindicated.

Potential interactions leading to increased blood pressure

Except when patients can be monitored for elevated blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitantly with drugs such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasopressors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Lactic acidosis

Lactic acidosis has been reported during treatment with linezolid. Patients who develop symptoms or signs of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully considered.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic) may occur. These effects are more common when the drug is used for more than 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants such as SSRIs, have been received. Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when the use of both linezolid and serotonergic agents is considered life-saving. In such cases, the patient should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If symptoms occur, the physician should consider discontinuing one or both agents. Withdrawal symptoms may occur after discontinuation of the serotonergic agent.

Hypnatremia and SIADH

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients receiving linezolid. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatremia, such as elderly patients or those taking medications that may reduce serum sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy and optic neuritis, sometimes progressing to vision loss, have been observed in patients receiving linezolid. Most of these patients received treatment for more than 28 days (the maximum recommended treatment duration).

All patients should be advised to report symptoms of visual disturbances, such as changes in visual acuity, color vision changes, blurred vision, or visual field defects. In such cases, prompt ophthalmologic evaluation is recommended. Patients receiving Lizezomak 600 for more than 28 days should have regular vision examinations.

If peripheral or optic neuropathy develops, the benefit of continuing linezolid therapy versus potential risks should be carefully considered.

The risk of neuropathies may be increased when linezolid is used to treat patients who are currently or recently have been treated with antibacterial agents for tuberculosis.

Seizures

Seizures have been reported in patients receiving linezolid therapy. In most cases, these patients had a history of seizures; therefore, patients should inform their physicians if they have previously experienced seizures.

MAO inhibitors

Linezolid is a non-selective, reversible MAO inhibitor. However, at doses used for antibacterial therapy, it does not have a significant inhibitory effect. Very limited data are available from drug interaction and safety studies regarding the use of linezolid in patients with underlying conditions and/or concomitant medications that pose certain risks due to MAO inhibition. Therefore, unless close patient monitoring is possible, use of linezolid is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use with tyramine-rich foods

Patients should be advised to avoid consuming large amounts of tyramine-rich foods (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia

Post-marketing reports indicate cases of symptomatic hypoglycemia with use of linezolid, a reversible non-selective MAO inhibitor, in diabetic patients receiving insulin or oral hypoglycemic agents. Hypoglycemic episodes have been associated with some MAO inhibitors in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned of the potential for hypoglycemic reactions during linezolid therapy.

If hypoglycemia occurs, dose reduction of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Superinfection

The effect of linezolid on normal flora has not been studied in clinical trials. Antibiotic use may occasionally lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical studies developed candidiasis associated with drug use. If superinfection occurs during treatment, appropriate measures should be taken.

Special patient groups

Linezolid should be used with caution and only when the expected benefit outweighs the potential risk in patients with severe renal impairment (see section "Dosage and administration").

Linezolid should be used only when the expected benefit outweighs the potential risk in patients with severe hepatic impairment (see section "Dosage and administration").

Gender

No dose adjustment is necessary based on gender.

Impairment of fertility

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately similar to those expected in humans. These changes were reversible.

The potential effect of linezolid on male reproductive function is unknown.

Clinical trials

The safety and efficacy of linezolid for use beyond 28 days have not been established.

Controlled clinical trials did not include patients with diabetic foot infections, pressure ulcers, ischemic lesions, severe burns, or gangrene. Therefore, experience with the use of linezolid for treatment of these conditions is limited.

Allergic reactions to soy lecithin:

The linezolid tablet contains soy lecithin. Soy lecithin may cause allergic reactions in patients with soy allergy.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free."

The tablet contains polyoxyl 40 hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Use during pregnancy or breastfeeding.

Use during pregnancy. Data on the use of Lizezomak 600 in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. A potential risk to humans exists. Lizezomak 600 should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Use during breastfeeding. Animal studies have shown that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during treatment with the drug.

Fertility

In animal studies, linezolid caused reduced fertility.

Ability to influence reaction speed when driving or operating machinery.

Patients should be warned of the possibility of dizziness or visual disturbances (see sections "Special precautions for use" and "Adverse reactions") during linezolid therapy and advised not to drive or operate machinery if these symptoms occur.

Dosage and Administration

The duration of treatment depends on the causative pathogen, site and severity of infection, as well as the clinical response to therapy.

The treatment duration recommendations provided below were used in clinical studies. For certain types of infections, a shorter duration of treatment may be appropriate, although this has not been evaluated in clinical trials.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been studied.

There is no need to increase the recommended doses or duration of treatment in infections associated with bacteremia.

Dosage recommendations according to indications are provided in the table below.

Patients whose treatment was initiated with intravenous linezolid infusions may be switched to oral linezolid therapy. In such cases, dose adjustment is not required, as the bioavailability of linezolid following oral administration is nearly 100%.

Doses recommended for adults and adolescents (aged 12 years and older)

Indications	Dosage and administration	Recommended duration of treatment (consecutive days)
	Adults and children (aged 12 years and older)
Nosocomial pneumonia	600 mg intravenously* or orally every 12 hours	10-14
Community-acquired pneumonia (particularly forms associated with bacteremia)
Complicated skin and soft tissue infections
Infections caused by vancomycin-resistant Enterococcus faecium, including infections associated with bacteremia	600 mg intravenously* or orally every 12 hours	14-28
Uncomplicated skin and soft tissue infections	Adults: 400 mg orally every 12 hours* Children aged 12 years and older: 600 mg orally every 12 hours	10-14

*- The drug should be used in another pharmaceutical form allowing appropriate dosing.

The maximum dose should not exceed 600 mg twice daily.

Use in elderly patients: dose adjustment is not required.

Use in patients with renal impairment: dose adjustment is not required.

Patients with severe renal impairment (particularly with creatinine clearance < 30 mL/min): dose adjustment is not required. Due to the unknown clinical significance of higher systemic exposure (up to 10-fold) to two major metabolites of linezolid in patients with severe renal impairment, the drug should be administered to these patients with particular caution and only when the expected benefit outweighs the potential risk.

Approximately 30% of the administered dose of linezolid is removed during a 3-hour hemodialysis session; therefore, the drug should be administered to such patients after dialysis. The major metabolites of linezolid are partially eliminated during hemodialysis, but their concentrations remain significantly higher after dialysis compared to those observed in patients with normal renal function or mild to moderate renal impairment.

Thus, linezolid should be used with particular caution in patients with severe renal impairment undergoing hemodialysis and only when the expected benefit of therapy outweighs the potential risk.

Currently, there is no clinical experience with the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis or other alternative treatments for renal failure (other than hemodialysis).

Use in patients with renal impairment: dose adjustment is not required. However, clinical data in this regard are limited; therefore, linezolid should be used in such patients only when the expected benefit of treatment outweighs the potential risk.

Children.

The drug is not recommended for children under 12 years of age.

Overdose.

No cases of overdose have been reported.

Treatment. No specific antidote is known.

In case of overdose, symptomatic treatment should be administered, including measures to support glomerular filtration rate. Approximately 30% of the administered dose is removed during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. The two primary metabolites of linezolid are also removed by hemodialysis.

Adverse Reactions

The information provided is based on data from clinical trials in which more than 2000 adult patients received the recommended doses of the medicinal product for up to 28 days.

The most commonly reported adverse reactions leading to discontinuation of the medicinal product were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

Additional adverse reactions reported after marketing authorization are listed below, categorized with an occurrence frequency of "frequency not known," as the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below according to the following frequency classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

Infections and infestations: common – candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; uncommon – antibiotic-associated colitis, including pseudomembranous colitis*, vaginitis.

Blood and lymphatic system disorders: common – thrombocytopenia*, anemia*†; uncommon – pancytopenia*, leukopenia*, neutropenia, eosinophilia; rare – sideroblastic anemia*; frequency not known – myelosuppression*.

Immune system disorders: rare – anaphylaxis.

Metabolism and nutrition disorders: uncommon – hyponatremia; rare – lactic acidosis*.

Psychiatric disorders: common – insomnia.

Nervous system disorders: common – headache, taste perversion (metallic taste), dizziness; uncommon – seizures*, peripheral neuropathy*, hypoaesthesia, paraesthesia; frequency not known – serotonin syndrome*.

Eye disorders: uncommon – optic neuropathy*, blurred vision*; rare – visual field defect*; frequency not known – optic neuritis*, vision loss*, change in visual sensation*, change in color perception*.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

Vascular disorders: common – arterial hypertension; uncommon – transient ischemic attack, phlebitis, thrombophlebitis.

Gastrointestinal disorders: common – diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disturbances or change in tongue color; rare – discoloration of tooth surface.

Hepatobiliary disorders: common – abnormalities in liver function tests, increased levels of ALT, AST, or alkaline phosphatase; uncommon – increased total bilirubin.

Skin and subcutaneous tissue disorders: common – pruritus, rash; uncommon – angioedema, urticaria, dermatitis, bullous skin lesions, hyperhidrosis; rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, hypersensitivity vasculitis; frequency not known – alopecia.

Renal and urinary disorders: common – increased blood urea nitrogen; uncommon – renal failure, increased creatinine, polyuria.

Reproductive system and breast disorders: uncommon – vulvovaginal disorders.

General disorders and administration site conditions: common – pyrexia, localized pain; uncommon – chills, fatigue, injection site pain, thirst.

Investigations. Chemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride. Hematology: common – increased neutrophil or eosinophil count, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – increased reticulocyte count, decreased neutrophil count.

* See section "Special Warnings and Precautions for Use".

** See sections "Contraindications" and "Interaction with Other Medicinal Products and Other Forms of Interaction".

† During controlled clinical trials in which linezolid was administered for up to 28 days, anemia occurred in 2.0% of patients. In a compassionate use program involving patients with life-threatening infections and comorbid conditions, the percentage of patients who developed anemia after receiving linezolid for ≤ 28 days was 2.5% (33 out of 1326), compared to 12.3% (53 out of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia attributed to the medicinal product requiring blood transfusion was 9% (3 out of 33) in patients treated for ≤ 28 days and 15% (8 out of 53) in those treated for > 28 days.

Adverse reactions associated with linezolid use, which were assessed in rare cases as severe reactions: localized abdominal pain, transient ischemic attack, and arterial hypertension.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets in a strip, 1 strip in a cardboard box;

10 tablets in a strip, 1, 6, or 10 strips in a cardboard box;

10 tablets in a blister, 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and place of business.

Village Theda, P.O. Lodhmayra, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.